Evaluation of the effect of hyperventilation in diabetic polyneuropathy on "threshold electrotonus" by threshold tracking method

The most common neurological complication of diabetes is distal symmetric polyneuropathy, which significantly impairs the health-related quality of life. The pathogenesis of diabetic polyneuropathy (PNP) involves multiple factors. The role of hyperglycemia-induced metabolic changes and structural changes such as demyelination in the peripheral nerve dysfunction as well as nodal and internodal ion channels is yet to be well established. Nerve conduction and axonal excitability studies are commonly employed to investigate the pathophysiology of many diseases, including diabetic polyneuropathy. The changes in the markers for axonal excitability of peripheral nerves can be examined through various maneuvers, and the axonal excitability findings associated with hyperventilation are expected to shed light on the mechanism of pathological changes occurring in the peripheral nerves in diabetic PNP. In this study, we aimed to determine the electrophysiological correlates of clinically observed resistance to hyperventilation in patients with diabetic PNP, and to identify any possible differences between diabetic patients and healthy controls in terms of pH sensitivity of nodal persistent Na channels. Our study included a sample of 47 subjects, consisting of 15 healthy controls and 32 patients with Type II Diabetes Mellitus [15 with PNP (PNP+) and 17 without PNP (PNP-)]. Fasting plasma glucose and HBA1C levels were measured, and nerve conduction studies were performed in all research participants. All participants were administered hyperventilation test for 25 minutes, and inquired about hyperventilation-related complaints before and after HPV testing. Using short TROND protocol in the left median nerve, motor axonal excitability studies were conducted before and after HPV. In all cases, venous blood samples were taken prior to HPV and at 15 minutes of HPV to study blood gases. We found no significant difference between the healthy controls and the diabetic patients with and without PNP in terms of axonal strength-duration time constant (SDTC) and rheobase. On the other hand, there were significant differences in the threshold electrotonus to depolarizing currents and recovery cycle of excitability, especially in the early period of supernormality and subnormality at 5 ms, which suggested greater depolarization in patients with polyneuropathy. At the end of HPV testing, the most prominent increase in the hyperventilation complaints scale was observed in healthy controls. The clinical response of healthy controls to hyperventilation was significantly stronger than that of the patient group. There were no significant differences between the patient groups. The control group had a significant decline in the rheobase during hyperventilation, and the increase observed in SDTC was not considered statistically significant. There were no significant changes in the threshold electrotonus during HPV, and in the recovery cycle, the changes included prolonged refractoriness at 2.5 ms, longer relative refractory period (RRP), and increased supernormality at 5 ms. From HPV data, we plotted a leftward shift in the stimulus-response curve of the DM group without PNP. No significant changes occurred in rheobase and SDTC. In threshold electrotonus, there were differences in depolarizing and hyperpolarizing currents. The RRP was longer, with increased refractoriness and subnormality at 2.5 ms. In the group with PNP stimulus for 50% of maximum decreased, plotting a leftward shift in the stimulus-response curve during HPV. After HPV, we observed changes in threshold electrotonus, suggesting that internodal K channels were affected. The lack of significant changes in the recovery cycle, SDTC and rheobase (p=0.05) during HPV testing indicated that nodal persistent Na channels were insensitive to pH in patients with diabetic polyneuropathy. In conclusion, we found that healthy controls and patients with no structural changes had similar axonal excitability markers, while patients with observed structural changes had significantly greater axonal depolarization. Along with the findings suggesting that internodal K channels were affected by changes in pH in diabetic patients, the insensitivity of nodal persistent Na channels was also demonstrated. Based on our study findings showing that diabetic patients had resistance to hyperventilation clinically similar to ischemia, we consider that this resistance has electrophysiological correlates. However, the drugs used for the treatment of diabetes mellitus should be taken into account while interpreting these results showing differences between healthy controls and diabetic patients with and without PNP